The global emergence of multidrug-resistant tuberculosis (MDR-TB) is an enormous public health threat and barrier to effective TB control. The rise in further drug resistance leading to pre-extensively drug-resistant (XDR) and XDR-TB is particularly alarming given the associated high mortality and poor treatment outcomes, especially compared to drug susceptible and even MDR-TB. The recent introduction of repurposed and newly discovered drugs offers promise in improving pre-XDR and XDR-TB treatment outcomes but critical knowledge gaps exist. There are scarce data on the performance of repurposed and novel drugs when used in combination, among patients with XDR-TB, rates of acquired drug resistance, and the pharmacokinetics and pharmacodynamics (PK/PD) of new drug regimens. The importance of TB drug PK/PD has recently been emphasized by studies among patients with drug susceptible TB; however, whether this is the case for new drug combinations among patients with pre-XDR and XDR-TB is unknown. The ability of repurposed and novel TB drugs to penetrate into the lung, the main site of disease, is also undetermined and will be vital information when designing effective regimens. We propose a prospective observational study to evaluate the PK/PD of novel TB drug regimens, including their cavitary penetration, among patients with pulmonary pre-XDR and XDR-TB from the country of Georgia. We hypothesize that optimal drug concentrations will be associated with a faster time to culture conversion and less acquired drug resistance. A better understanding of the clinical pharmacology of new drug regimens will help ensure optimal and responsible use of new drug combinations and thus improve pre-XDR and XDR-TB treatment. The Specific AIMs of this proposal include: 1) To determine the serum pharmacokinetics of newly introduced drugs [bedaquiline (BDQ), linezolid (LNZ), and clofazimine (CFZ)] among patients with pulmonary pre-XDR and XDR-TB. We will enroll 60 patients receiving this novel drug combination at the National Center for TB and Lung Diseases in Tbilisi, Georgia. PK modeling will be performed to identify predictors of optimal serum drug concentrations. 2) To investigate the association of BDQ, LNZ and CFZ serum pharmacokinetics with clinical outcomes among patients with pre-XDR and XDR-TB in AIM 1. Intensive PK sampling will be performed at 3-6 weeks of treatment along with MIC testing of positive cultures. We will utilize whole genome sequencing (WGS) to assess genetic determinants of resistance. Our results will provide novel data on the optimal concentrations of newly introduced drug regimens as well as vital information on toxicities, and drug-drug interactions. 3) To determine the tissue pharmacokinetics of BDQ, LNZ, and CFZ in tuberculous cavitary lung among patients with pre-XDR and XDR-TB undergoing adjunctive surgical therapy. Utilizing a new cohort of 10 patients and an innovative technique of microdialysis, we will provide the first data on cavitary penetration and whether the cavity is a site of AR to these newly introduced drugs.